The potential role of membrane lipids in the regulation of signal transmission has been increasingly recognized. Lipid research in psychiatric diseases has not yet received adequate attention. Abnormalities of phospholipid and fatty acid composition have been previously reported in patients with schizophrenia. Many of these studies, however, were flawed by inadequate clinical design, diagnostic criteria, and lipid methodology. Although the existence of such abnormalites in schizophrenia remains unclear, there are enough preliminary data to warrant further investigations. The major goals of this proposal are thus: 1) to assess membrane structural abnormalities by characterizing red blood cell (RBC) phospholipid subclasses and its molecular species; 2) to test whether a defect in regulation of RBC phospholipid metabolism by deacylation and reacylation processes is present in schizophrenia; and 3) to study the receptor-stimulated hydrolysis of platelet inositol phospholipids. Using updated biochemical and clinical methodology, we will systematically study lipid and other biochemical parameters of plasma. RBC, and platelets of a carefully diagnosed group of schizophrenic patients (n=80), of a non-schizophrenic psychiatric control group (n=30), and of age- matched control subjects (n=50). Three blood samples will be obtained from the same patient at different time points during the course of neuroleptic treatment (greater than 14 weeks), a 5- week wash-out period, and a 10-week follow-up study. To determine whether lipid alterations are present in clinically stable, "drug-free" schizophrenic patients, data from patients who do not relapse at the end of a 5-week (or 15-week) "wash-out" period will be compared to those obtained from normal and psychiatric control subjects. A number of patient demographic and diagnostic characteristics as possible sources of variance will be assessed. Differences within the schizophrenic subtypes will be evaluated. To assess the haloperidol-induced alterations, data from patients who do not relapse at the end of the 5-week (or 15- week) "wash-out" period will be compared to data from these same individuals at the end of the neuroleptic treatment phase. Insights gained above will provide further understanding of the molecular mechanism(s) which might regulate the metabolic defects present in schizophrenia. The identification of potential molecular markers for schizophrenia may also help to identify individuals at risk for this disorder, which would have significant implications for the genetic study of schizophrenia, and could potentially serve as a means for segregating this heterogeneous disorder into more homogeneous subgroups.